Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine.

AIM: The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis. METHODS: We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥ 3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (-2 days to +3 days of menses onset) and ≥ 5 moderate or severe migraines per month prior to entering the trial. RESULTS: Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥ 3x normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥ 8× normal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference -0.5 day (95% CI: -1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference -0.4 day (95% CI: -0.5, -0.2), nominal p < 0.001). CONCLUSIONS: Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.

Combination treatment for menstrual migraine and dysmenorrhea using sumatriptan-naproxen: two randomized controlled trials.

OBJECTIVE: To evaluate the efficacy and tolerability of sumatriptan-naproxen during the mild pain phase of a single menstrual migraine attack associated with dysmenorrhea. METHODS: Two replicate randomized, multicenter, double-blind, placebo-controlled, trials of adults with menstrual migraine and dysmenorrhea were conducted. Participants treated their menstrual migraine attack during the mild pain phase (within 1 hour of onset) with sumatriptan 85 mg and naproxen sodium 500 mg in a single fixed-dose formulation (sumatriptan-naproxen) or placebo. The primary endpoint was 2-hour pain-free response. RESULTS: Sumatriptan-naproxen was statistically superior to placebo in both studies (n=311, Study 1; n=310, Study 2) for 2-hour and, 2- to 24-hour sustained pain-free response, use of headache and menstrual rescue medications, and several nonpain menstrual symptom categories. Two-hour pain-free rates were Study 1, 42% compared with 23%, and Study 2, 52% compared with 22%, P<.001. Two- to 24-hour sustained pain-free rates were Study 1, 29% compared with 18%, P=.022; Study 2, 38% compared with 10%, P<.001. Headache and menstrual medication rates were Study 1, 37% compared with 53%, P=.005; Study 2, 31% compared with 69%, P<.001. Women treated with sumatriptan-naproxen continued to be pain free through 48 hours compared with placebo: Study 1, 26% compared with 17%, P=.040; Study 2, 28% compared with 8%, P<.001. No serious adverse events were reported in either study; nausea and dizziness were the most frequently reported adverse events. CONCLUSION: Sumatriptan-naproxen provided an effective pain-free response at 2 hours, which was maintained up to 48 hours in menstrual migraineurs with dysmenorrhea. Sumatriptan-naproxen was well-tolerated and resulted in decreased rescue medication use and relief of nonpainful menstrual symptoms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00329459 and NCT00329355 LEVEL OF EVIDENCE: I.

Rizatriptan efficacy in ICHD-II pure menstrual migraine and menstrually related migraine.

OBJECTIVE: To examine the efficacy of rizatriptan for the treatment of pure menstrual migraine (PMM). BACKGROUND: In 2004, the International Headache Society proposed new research criteria for menstrual migraine (International Classification of Headache Disorders [ICHD-II]). Two subtypes were defined: PMM, in which attacks occur exclusively with menstruation, and menstrually related migraine (MRM), in which attacks may also occur at other times of the cycle. METHODS: The 2 protocols (MM1 and MM2) were identical randomized, double-blind studies. Adult patients with ICHD-II menstrual migraine were assigned to either rizatriptan 10-mg tablet or placebo (2:1). Patients were to treat a single menstrual migraine attack of moderate or severe pain intensity. This prospectively planned substudy pooled data from patients with a diagnosis of PMM from both studies. The primary substudy endpoint was 2-hour pain relief. Efficacy data were summarized for patients with a diagnosis of MRM. RESULTS: Of 707 (MM1: 357, MM2: 350) patients treated in the study, 146 patients (MM1: 81, MM2: 65) had a diagnosis of PMM. The percentage of patients reporting 2-hour pain relief was significantly greater for rizatriptan than for placebo for both PMM (73% vs 50%, P = .006) and MRM subgroups (71% vs 52%, P < .001). Most other efficacy endpoints favored rizatriptan compared with placebo in patients with either PMM or MRM. CONCLUSION: Rizatriptan 10 mg was superior to placebo for the treatment of PMM, as measured by 2-hour pain relief. Rizatriptan was also effective for the treatment of MRM and for relief of migraine-associated symptoms for both headache subtypes.

Menstrual-related pain conditions: dysmenorrhea and migraine.

Menstrual disorders affect millions of women in the United States and represent an important health burden. The most common menstrual disorders are dysmenorrhea and headache; these conditions are leading causes of work or school absenteeism and substantially impact quality of life. Headache associated with menses is often migraine and referred to as menstrual migraine. Although the pathogenesis of menstrual-related pain conditions is not fully understood, menstrual-related overproduction of prostaglandins is implicated in the pathophysiology of both menstrual migraine and dysmenorrhea. In clinical practice, nonsteroidal anti-inflammatory drugs (NSAIDs) are considered the first-line therapeutic option for managing pain associated with dysmenorrhea. NSAIDs also play a role in the acute treatment and intermittent prophylaxis of migraine. Triptans, a class of highly selective serotonin receptor agonists, represent the gold standard for acute treatment of migraine. In addition, hormone therapy is effective in many cases for treating dysmenorrhea and may be beneficial in the management of menstrual migraine. Thus, overlapping treatment regimens may be advantageous in treating the coexisting menstrual-related pain conditions of dysmenorrhea and migraine.

The use of triptans in the management of menstrual migraine.

Many women experience headaches, including migraine, in association with their menstrual cycles. Although definitions vary, menstrual migraine generally refers to migraine without aura that occurs within several days prior to and several days after the onset of menses. Although menstrual migraine has been reported to be more difficult to treat than other types of migraines, there is no evidence from controlled clinical trials to support this assertion. Thus, the pharmacological treatment of menstrual migraine should be similar to that of other types of migraines, except with respect to the use of hormonal manipulations to treat menstrual migraine. Serotonin 5-HT(1B/1D) receptor agonists (triptans) are effective for the acute treatment of both menstrual and non-menstrual migraines. When used as acute therapy, a triptan should be administered early, when the headache is still mild in severity. Ideally, an acute therapy will provide rapid and complete pain relief with no disability. Some patients may require preventive therapy for menstrual migraine based on suboptimal response to an adequate trial of acute therapy. Patient diaries that record headache onset, relationship to the menstrual cycle and treatment response through three complete cycles will allow accurate prediction of the onset of menstrual migraine; this information is also needed to make decisions about timing of intermittent preventive therapy. The goals of intermittent preventive therapy are to reduce the frequency, duration and intensity of menstrual migraine attacks. Clinical studies show that triptans are effective when used as either acute therapy or as intermittent preventive therapy for menstrual migraine. Sumatriptan and zolmitriptan have been evaluated in prospective, randomised, controlled trials for acute treatment. Retrospective analyses and open-label studies also support the use of other triptans as acute therapy. In addition, sumatriptan, frovatriptan, naratriptan and zolmitriptan have been evaluated as intermittent preventive therapy in prospective studies. Thus, data from clinical studies indicate that triptans are effective for the treatment of menstrual migraine.

Pain-free results with sumatriptan taken at the first sign of migraine pain: 2 randomized, double-blind, placebo-controlled studies.

OBJECTIVE: To evaluate the efficacy and tolerability of sumatriptan, 50-mg and 100-mg tablets, compared with placebo for treatment of migraine at the first sign of pain. PATIENTS AND METHODS: Two identical multicenter randomized, double-blind, placebo-controlled, single-attack studies were conducted from May through November 2000 in adults (aged 18-65 years). Patients treated migraine at the first sign of pain, while pain was mild, but not more than 2 hours after onset with oral sumatriptan, 50 mg or 100 mg, or matching placebo. The primary end point was pain-free relief at 2 hours after treatment with 50 mg of sumatriptan compared with placebo. RESULTS: There were 354 patients in study 1 and 337 patients in study 2. Significantly more patients treated with sumatriptan, 50 mg and 100 mg, were completely free from pain 2 and 4 hours after treatment vs patients treated with placebo (at 2 hours, 50% and 57% vs 29%; at 4 hours, 61% and 68% vs 30%; for both, P < .001). Also, significantly more patients treated with sumatriptan, 50 mg and 100 mg, were migraine-free (no pain or associated symptoms) vs those treated with placebo at 2 and 4 hours after treatment (at 2 hours, 43% and 49% vs 24%; at 4 hours, 54% and 63% vs 28%; for both, P < .001). The incidence of overall adverse events was low with the 50- and 100-mg dose of sumatriptan (placebo, 7%; sumatriptan at 50 mg, 14%; sumatriptan at 100 mg, 16%). CONCLUSIONS: Treatment of migraine at the first sign of pain with sumatriptan, 50-mg and 100-mg tablets, provides superior pain-free relief at 2 and 4 hours after treatment compared with placebo. Results of these studies suggest that sumatriptan at 100 mg may be more efficacious than at 50 mg when used in the early treatment paradigm. Because these studies were not powered to detect statistical differences between active doses, studies to investigate this finding are warranted.

Management of menstrual migraine.

BACKGROUND: Migraine is more prevalent in women than men. Hormonal changes can influence the occurrence of migraine, particularly related to the menstrual cycle. Menstrual migraine may require both acute and preventive treatment. REVIEW SUMMARY: Gender differences in migraine may be a result of variations in the central nervous system of men and women as well as the effects of estrogen. Migraine attacks occurring in the perimenstrual period respond well to acute treatment with triptans. Hormonal manipulation may reduce migraine occurrence, especially when related to hormonal fluctuations in the perimenstrual period. CONCLUSIONS: Effective migraine management requires an understanding of the unique epidemiologic and pathophysiological factors affecting women. An understanding of associated hormonal influences facilitates development of individualized treatment plans.

Almotriptan versus sumatriptan in migraine treatment: direct medical costs of managing adverse chest symptoms.

OBJECTIVE: Triptans, a popular class of drugs for treatment of migraine headaches, can cause adverse events including chest symptoms. This study estimated the direct medical costs of managing chest symptoms in patients treated for acute migraine with almotriptan or sumatriptan using an economic model. METHODS: The economic model of this study combined data from a randomized clinical trial that compared almotriptan with sumatriptan and data from a practice pattern survey of physicians. The pertinent clinical evaluation period was the time immediately after administration of the first medication dose. The model was developed from the perspective of a managed care payer. RESULTS: The average direct medical cost of managing chest symptoms that appeared after the first dose of an oral triptan was $0.22 for patients treated with almotriptan and $1.64 for patients treated with sumatriptan, a difference of $1.42 per patient. CONCLUSION: Relative to sumatriptan, treatment with almotriptan is likely to reduce patient care costs associated with chest symptom adverse events.

Relieving migraine pain: sorting through the options.

Although triptans are a major advance in the treatment of migraine, the optimal approach for acute treatment involves a combination of lifestyle modifications, nonpharmacologic symptom relief, and drug therapy.

Women and headache: a treatment approach based on life stages.

Effective headache management in women requires an understanding of the unique epidemiologic and pathophysiologic factors affecting women. We present preventive, abortive, and nonpharmacologic approaches to headache treatment that vary with the chronologic and hormonal stages of a woman's life, with special attention to headache during pregnancy and later in life.

Clinical advances in the preventive treatment of migraine.

Evidence is emerging on the physiological processes underlying episodic migraine and the rationale for preventive treatment. Objectives for preventive treatment include limiting future pain and disability and potentially modulating the course of disease progression. Many factors influence medication choice for patients such as migraine type, patient preference, co-existing conditions, and medication side effects. In this paper, frequently prescribed treatment options for migraine prevention are reviewed. Most headache preventive medications treat other medical disorders and are found serendipitously to be beneficial in migraine or other headache disorders. A new treatment option is topiramate, with proven safety and efficacy across the largest controlled migraine prevention trials conducted to date. New clinical information is enhancing patient care and enabling clinicians to ease the burden of migraine worldwide.

Relief of menstrual symptoms and migraine with a single-tablet formulation of sumatriptan and naproxen sodium.

BACKGROUND: Dysmenorrhea and menstrual migraine may share a common pathogenic pathway. Both appear to be mediated, in part, by an excess of prostaglandin production that occurs during menstruation. METHODS: Data were pooled from two replicate randomized controlled trials of 621 adult menstrual migraineurs with dysmenorrhea who treated migraine with sumatriptan-naproxen or placebo. Along with headache symptoms, nonpain menstrual symptoms (bloating, fatigue, and irritability) and menstrual pain symptoms (abdominal and back pain) were recorded at the time periods of 30 minutes and 1, 2, 4, and 4-24 hours. Relief of menstrual symptoms was compared using a Cochran-Mantel-Haenszel test. Logistic regression was used to determine the odds of a headache response with increasing numbers of moderate to severe dymenorrheic symptoms. RESULTS: Sumatriptan-naproxen was superior to placebo for relief of tiredness, irritability, and abdominal pain at the time periods of 2, 4, and 4-24 hours (p≤0.023); back pain at the time periods of 4 and 4-24 hours (p≤0.023); and bloating at 4-24 hours endpoint (p=0.01). The odds ratios (ORs) of attaining migraine pain freedom for 2 hours and for sustained 2-24 hours decreased as moderate to severe dysmenorrhea symptoms increased with sumatriptan-naproxen versus placebo. CONCLUSIONS: Treatment with sumatriptan-naproxen may provide relief of menstrual symptoms and migraine in female migraineurs with dysmenorrhea. The presence of moderate to severe dysmenorrhea symptoms is associated with decreased response rates for menstrual migraine, suggesting that the co-occurrence of these disorders may negatively impact the results of migraine-abortive therapy.

A review of the 5-HT1B/1D agonist rizatriptan: update on recent research and implications for the future.

BACKGROUND: Among the 5-HT(1B/1D) agonists or 'triptans,' which are considered first-line therapy for acute migraine, rizatriptan has emerged as one of the most efficacious. OBJECTIVE: Several comprehensive reviews of rizatriptan are available in the literature; the aim of this paper is to review the most current research with rizatriptan. METHODS: The scope of the review addresses current topics of clinical interest, including studies of time to pain relief, effect of early administration, use in combination with other drugs, and tolerability updates, as well as trials of rizatriptan in certain subpopulations such as patients with menstrual migraine, patients with motion sickness and pediatric patients. CONCLUSION: In the context of these newly available data, the potential for expansion of the role of rizatriptan in the clinic is evaluated.

Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies.

BACKGROUND: In a pilot study, naratriptan was significantly more effective than placebo in preventing menstrually related migraine (MRM) when given as 1 mg twice daily for 5 days beginning 2 days before the predicted onset of MRM for up to 4 menstrual cycles. OBJECTIVE: To evaluate the efficacy and tolerability of naratriptan for short-term prevention of MRM in 2 large, identically designed, randomized, double-blind, placebo-controlled, parallel-group studies. METHODS: MRM was defined as any migraine beginning during the perimenstrual period (PMP). By definition, the PMP consisted of Days -2, -1, 1, 2, 3, and 4, with Day 1 being the first day of menstrual flow. Adult women were eligible if they reported a history of MRM, had regular menstrual cycles, and could predict within 2 days both the onset of menstrual flow and MRM. The studies comprised a baseline phase and a treatment phase. During the baseline phase, patients prophylactically treated their first PMP after the screening visit with single-blind placebo. Patients who documented an MRM while receiving placebo were eligible for the treatment phase. During the treatment phase, patients were randomized to receive either naratriptan 1 mg twice daily or placebo beginning 3 days before the predicted onset of MRM for a total of 6 days for 4 PMPs or 6 months, whichever occurred sooner. The primary efficacy endpoint was the mean percentage of treated PMPs without MRM per patient. Secondary efficacy endpoints included the percentage of patients who were free of MRM during all treated PMPs, the median number of days with MRM over 4 PMPs, and patient satisfaction. Safety and tolerability measures included adverse events, standard clinical laboratory tests, and vital signs. RESULTS: The intent-to-treat population was 287 in Study 1 (149 in the naratriptan group and 138 in the placebo group) and 346 in Study 2 (173 in each treatment group). Approximately 20% of randomized patients in each treatment group in Study 1 and 10% in each treatment group in Study 2 withdrew prematurely from the studies over the 4-month treatment period. The mean percentage of PMPs without MRM per patient was 38% and 34% among naratriptan-treated patients treating at least 1 PMP compared with 29% and 24% among placebo-treated patients in each respective study (P < .05 naratriptan vs placebo for both studies). Efficacy of naratriptan did not vary as a function of age, use of oral contraceptives, or use of migraine prophylaxis. More patients who had received naratriptan reported attacks posttreatment compared to patients who had received placebo. Among patients treating at least 1 PMP, the percentage of patients with no MRM in any treated PMP was significantly (P < .05) higher in the naratriptan group (11%; 19/173) than the placebo group (3%; 6 of 173) in Study 2. There were no differences in the percentages of patients with no MRM in any treated PMP in Study 1. The number of MRM days per patient across 4 PMPs was significantly lower in the naratriptan group than in the placebo group in both studies (median 5.0 days vs 6.5 days in Study 1 [P= .005] and 5.3 days vs 6.0 days in Study 2 [P= .018]). Significantly more patients receiving naratriptan were satisfied with the ability of naratriptan to control MRM either by preventing their occurrence or reducing their severity or duration compared with patients receiving placebo. No single drug-related adverse event was reported by more than 2% of patients in a treatment group in either study, and no serious drug-related adverse events were reported. CONCLUSIONS: Naratriptan 1 mg twice daily for 6 days per month is effective and well tolerated when used for short-term prevention of MRM. More patients receiving naratriptan than placebo were satisfied with treatment. The observed increase in posttreatment attacks needs further study.

Menstrual Migraine.

The initial treatment of menstrual migraine (MM) should be the same as that of migraine that occurs at any other time during the month and should include lifestyle modifications and the use of appropriate acute therapies aimed at decreasing attack symptoms, duration, and disability. If results of acute therapy are incomplete or unsatisfactory, then preventive strategies may be required. Comorbidities may, however, influence choice of preventive therapy or accelerate initiation of preventive therapy. Comorbid dysmenorrhea, menometrorrhagia, and endometriosis argue for early use of hormonal therapies. Hormonal strategies may be appropriate because the premenstrual decline in estradiol concentration predictably precipitates MM, and targeting and preventing this decline can decrease headache occurrence. Continuous combined hormonal contraceptives can reduce hormone fluctuations and, for some MM sufferers, can deliver more than contraceptive benefits. Nonsteroidal anti-inflammatory drugs are appropriate for treatment of co-occurring dysmenorrhea or when hormonal strategies are contraindicated; their efficacy may be caused partly by the role of prostaglandins in MM and dysmenorrhea. As with the use of hormonal therapy, use of nonsteroidal anti-inflammatory drugs allows for treatment of breakthrough headache with triptans. Results of clinical trials suggest that daily use of triptans in the menstrual window may bring about as much as 50% reduction in headache frequency, but such use still requires acute treatment of breakthrough headache and adherence to daily triptan limits. Use of this strategy requires that headache occurrence be highly predictable.

Rofecoxib in the prevention of perimenstrual migraine: an open-label pilot trial.

OBJECTIVE: To investigate the effectiveness of rofecoxib in the prevention of perimenstrual migraine. BACKGROUND: Nonsteroidal anti-inflammatory drugs have demonstrated benefit in reducing the frequency and intensity of menstrual migraine when administered perimenstrually. Anti-inflammatory drugs, however, may not be well tolerated and can produce gastrointestinal irritation. Rofecoxib, a selective cyclooxygenase-2 inhibitor, has anti-inflammatory and analgesic properties, and a significantly improved gastrointestinal tolerability profile. METHODS: A pilot study was conducted in which patients with a history of menstrually associated migraine and experiencing at least one migraine monthly during the perimenstrual period were enrolled. Patients who completed a baseline diary for the first month were randomized to receive either rofecoxib 25 mg or 50 mg daily for 10 days, starting 5 days before menstrual flow. Headaches experienced during this 10-day period were recorded in the patient's diary. Patients continued rofecoxib for 2 consecutive menstrual cycles. Mean migraine frequency, intensity, and duration as well as patient's level of functioning during the 2 cycles were compared with baseline. RESULTS: Fourteen patients completed baseline and rofecoxib dosing for 2 menstrual cycles. Mean migraine frequency decreased from 5.6 to 2.6 migraines per menstrual cycle (P=.005). Eight (57%) of 14 patients had a > or = 50% reduction in headache frequency. No significant improvement in headache intensity, duration, and functional impairment were observed. Both doses of rofecoxib were well tolerated with no statistical difference in patient response between the doses. CONCLUSION: Rofecoxib at a perimenstrual daily dose of 25 or 50 mg demonstrated a significant reduction in frequency of perimenstrual migraine. A double-blind, placebo-controlled trial of rofecoxib in the prevention of perimenstrual migraine is warranted.

Efficacy of topiramate in migraine prophylaxis: a retrospective chart analysis.

OBJECTIVE: Topiramate, a broad-spectrum anticonvulsant with multiple mechanisms of action, may be effective in preventing migraine headaches. We report the results of a retrospective chart review of patients treated with topiramate for prophylaxis of migraine. METHODS: Patients with a diagnosis of migraine who had at least one follow-up visit after > or =4 weeks on topiramate were eligible; 69 patients (56 women and 13 men) aged 18 to 68 years met these criteria. Charts were reviewed for frequency of mild or moderate/severe headaches at the start of topiramate (baseline) and at all subsequent visits up to 24 weeks. RESULTS: The 28-day frequency of moderate/severe migraines declined significantly from baseline to end of treatment (10.6 +/- 8.4 to 7.4 +/- 7.7, respectively; P = 0.0004), whereas that of mild headaches did not demonstrate a significant change (from 11.8 +/- 8.9 to 11.0 +/- 10.0). Among the 38 patients who had not responded previously to >or =9 preventive medications, the monthly frequency of moderate/severe (but not mild) headaches decreased significantly from baseline to end of treatment. Patients who previously had not responded to <9 prior medications experienced significant declines in both mild and moderate/severe headaches. The most common adverse events were paresthesias, drowsiness, diarrhea, decreased appetite, and weight loss. Twenty-seven patients discontinued topiramate therapy, 20 as a result of adverse events and 7 due to lack of response. CONCLUSION: Topiramate may be effective in reducing the frequency of both mild and moderate/severe migraine headaches. In particular, topiramate may offer relief to patients with moderate/severe migraines who do not respond to other treatments.